Skip to main content
SpringerLink
Log in

Evolution of Alzheimer’s disease pathogenesis conception

  • Gerontology
  • Published:
Moscow University Biological Sciences Bulletin Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that becomes a cause of dementia during atrophic brain changes. There are two distinguished forms of AD: familial early-onset form (FAD, approximately 5% of all cases, develops before age 65, most commonly 40–50) and sporadic late-onset form (SAD, approximately 95% of all cases, develops after 65). Identification of genetic determinants of FAD development and evidence of amyloid-beta peptide’s (Aβ) neurotoxicity as a central event in the cascade of pathological processes significantly expanded the conception of molecular and genetic mechanisms of the disease. However, the question of whether or not the accumulation of Aβ is the triggering factor of more widespread SAD remains open. There are a growing number of arguments for Aβ overproduction being the secondary, concomitant event of AD pathological processes: synaptic failure, hyperphosphorylation of tau protein, neuroinflammation, neuronal loss, and cognitive decline. As one of triggering risk factors of AD development, mitochondrial dysfunction is considered, with the decrease in ATP synthesis and oxidative stress becoming the consequences. However, the specific molecular and genetic mechanisms of AD remain unclear. This is caused by the lack of relevant animal models for studying mechanisms of the disease and objective estimation of pathogenically justified methods of AD prevention and treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Querfurth, H.W. and LaFerla, F.M., Alzheimer’s disease, N. Engl. J. Med., 2010, vol. 362, no. 4, pp. 329–344.

    Article  CAS  PubMed  Google Scholar 

  2. Morley, J.E., Armbrecht, H.J., Farr, S.A., and Kumar, V.B., The senescence accelerated mouse (SAMP8) as a model for oxidative stress and Alzheimer’s disease, Biochim. Biophys. Acta, 2012, vol. 1822, no. 5, pp. 650–656.

    Article  CAS  PubMed  Google Scholar 

  3. Drachman, D.A., The amyloid hypothesis, time to move on: amyloid is the downstream result, not cause, of Alzheimer’s disease, Alzheimer’s Dementia, 2014, vol. 10, no. 3, pp. 372–380.

    Google Scholar 

  4. Ridge, P.G., Ebbert, M.T., and Kauwe, J.S., Genetics of Alzheimer’s disease, Biomed. Res. Int., 2013, vol. 2013, artic. 254954.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Guerreiro, R., Bras, J., Toombs, J., Heslegrave, J., Hardy, J., and Zetterberg, H., Genetic variants and related biomarkers in sporadic Alzheimer’s disease, Curr. Genet. Med. Rep., 2015, vol. 3, no. 1, pp. 19–25.

    Article  PubMed  PubMed Central  Google Scholar 

  6. O’Brien, R.J. and Wong, P.C., Amyloid precursor protein processing and Alzheimer’s disease, Annu. Rev. Neurosci., 2011, vol. 34, pp. 185–204.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Puzzo, D. and Arancio, O., Amyloid-ß peptide: Dr. Jekyll or Mr. Hyde?, J. Alzheimer’s Dis., 2013, vol. 33, no. S1, pp. S111–S120.

    Google Scholar 

  8. Jayadev, S., Leverenz, J.B., Steinbart, E., Stahl, J., Klunk, W., Yu, C.E., and Bird, T.D., Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2, Brain, 2010, vol. 133, no. 4, pp. 1143–1154.

    Article  PubMed  PubMed Central  Google Scholar 

  9. DeMattos, R.B., Cirrito, J.R., Parsadanian, M., May, P.C., O’Dell, M.A., Taylor, J.W., Harmony, J.A., Aronow, B.J., Bales, K.R., Paul, S.M., and Holtzman, D.M., ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular abeta metabolism in vivo, Neuron, 2004, vol. 41, no. 2, pp. 193–202.

    Article  CAS  PubMed  Google Scholar 

  10. Thambisetty, M., An Y., Kinsey, A., Koka, D., Saleem, M., Güntert, A., Kraut, M., Ferrucci, L., Davatzikos, C., Lovestone, S., and Resnick, S.M., Plasma clusterin concentration is associated with longitudinal brain atrophy in mild cognitive impairment, Neuroimage, 2012, vol. 59, no. 1, pp. 212–217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jones, L., Holmans, P.A., Hamshere, M.L., et al., Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease, PLoS One, 2010, vol. 5, no. 11, p. e13950.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Armstrong, R.A., The pathogenesis of Alzheimer’s disease: a reevaluation of the “amyloid cascade hypothesis”, Int. J. Alzheimer’s Dis., 2011, vol. 2011, artic. 630865.

    CAS  Google Scholar 

  13. Cruchaga, C., Chakraverty, S., Mayo, K., et al., Rare variants in APP, PSEN1 and PSEN2 increase risk for ADin late-onset Alzheimer’s disease families, PLoS One, 2012, vol. 7, no. 2, p. e31039.

    CAS  Google Scholar 

  14. Hardy, J. and Selkoe, D.J., The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics, Science, 2002, vol. 297, no. 5580, pp. 353–356.

    Article  CAS  PubMed  Google Scholar 

  15. Kayed, R., Head, E., Thompson, J.L., McIntire, T.M., Milton, S.C., Cotman, C.W., and Glabe, C.G., Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis, Science, 2003, vol. 300, no. 5618, pp. 486–489.

    Article  CAS  PubMed  Google Scholar 

  16. Walsh, D.M. and Selkoe, D.J., A beta oligomers—a decade of discovery, J. Neurochem., 2007, vol. 101, no. 5, pp. 1172–1184.

    Article  CAS  PubMed  Google Scholar 

  17. Shankar, G.M., Li, S., Mehta, T.H., Garcia-Munoz, A., Shepardson, N.E., Smith, I., Brett, F.M., Farrell, M.A., Rowan, M.J., Lemere, C.A., Regan, C.M., Walsh, D.M., Sabatini, B.L., and Selkoe, D.J., Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory, Nat. Med., 2008, vol. 14, no. 8, pp. 837–842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. El Khoury, J., Toft, M., Hickman, S.E., Means, T.K., Terada, K., Geula, C., and Luster, A.D., Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease, Nat. Med., 2007, vol. 13, no. 4, pp. 432–438.

    Article  PubMed  Google Scholar 

  19. Qiu, W.Q., Walsh, D.M., Ye, Z., Vekrellis, K., Zhang, J., Podlisny, M.B., Rosner, M.R., Safavi, A., Hersh, L.B., and Selkoe, D.J., Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation, J. Biol. Chem., 1998, vol. 273, no. 49, pp. 32730–32738.

    Article  CAS  PubMed  Google Scholar 

  20. Kanemitsu, H., Tomiyama, T., and Mori, H., Human neprilysin is capable of degrading amyloid beta peptide not only in the monomeric form but also the pathological oligomeric form, Neurosci. Lett., 2003, vol. 350, no. 2, pp. 113–116.

    Article  CAS  PubMed  Google Scholar 

  21. Szabò, I., Leanza, L., Gulbins, E., and Zoratti, M., Physiology of potassium channels in the inner membrane of mitochondria, Pflügers Arch., 2012, vol. 463, no. 2, pp. 231–246.

    Article  PubMed  Google Scholar 

  22. Chaturvedi, R.K. and Flint M., Beal M., Mitochondrial diseases of the brain, Free Radic. Biol. Med., 2013, vol. 63, pp. 1–29.

    Article  CAS  PubMed  Google Scholar 

  23. Krstic, D. and Knuesel, I., Deciphering the mechanism underlying late-onset Alzheimer disease, Nat. Rev. Neurol., 2013, vol. 9, no. 1, pp. 25–34.

    Article  CAS  PubMed  Google Scholar 

  24. Roth, M., Tomlinson, B.E., and Blessed, G., Correlation between scores for dementia and counts of ‘senile plaques’ in cerebral grey matter of elderly subjects, Nature, 1966, vol. 209, no. 5018, pp. 109–110.

    Article  CAS  PubMed  Google Scholar 

  25. Spires-Jones, T.L. and Hyman, B.T., The intersection of amyloid beta and tau at synapses in Alzheimer’s disease, Neuron, 2014, vol. 82, no. 4, pp. 756–771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Khlistunova, I., Biernat, J., Wang, Y., Pickhardt, M., von Bergen, M., Gazova, Z., Mandelkow, E., and Mandelkow, E.M., Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs, J. Biol. Chem., 2006, vol. 281, no. 2, pp. 1205–1214.

    Article  CAS  PubMed  Google Scholar 

  27. Price, J.L., McKeel, D.W., Buckles, V.D., et al., Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease, Neurobiol. Aging, 2009, vol. 30, no. 7, pp. 1026–1036.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Spires-Jones, T.L., Stoothoff, W.H., de Calignon, A., Jones, P.B., and Hyman, B.T., Tau pathophysiology in neurodegeneration: a tangled issue, Trends Neurosci., 2009, vol. 32, no. 3, pp. 150–159.

    Article  CAS  PubMed  Google Scholar 

  29. Terry, R.D., Masliah, E., Salmon, D.P., Butters, N., DeTeresa, R., Hill, R., Hansen, L.A., and Katzman, R., Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment, Ann. Neurol., 1991, vol. 30, no. 4, pp. 572–580.

    Article  CAS  PubMed  Google Scholar 

  30. Wu, H.Y., Hudry, E., Hashimoto, T., Kuchibhotla, K., Rozkalne, A., Fan, Z., Spires-Jones, T., Xie, H., Arbel-Ornath, M., Grosskreutz, C.L., Bacskai, B.J., and Hyman, B.T., Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation, J. Neurosci., 2010, vol. 30, no. 7, pp. 2636–2649.

    CAS  PubMed  Google Scholar 

  31. Balietti, M., Giorgetti, B., Casoli, T., Solazzi, M., Tamagnini, F., Burattini, C., Aicardi, G., and Fattoretti, P., Early selective vulnerability of synapses and synaptic mitochondria in the hippocampal CA1 region of the Tg2576 mouse model of Alzheimer’s disease, J. Alzheimer’s Dis., 2013, vol. 34, no. 4, pp. 887–896.

    CAS  Google Scholar 

  32. Qu, J., Nakamura, T., Cao, G., Holland, E.A., McKercher, S.R., and Lipton, S.A., S-Nitrosylation activates cdk5 and contributes to synaptic spine loss induced by beta-amyloid peptide, Proc. Natl. Acad. Sci. U. S. A., 2011, vol. 108, no. 34, pp. 14330–14335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. D’Amelio, M., Cavallucci, V., Middei, S., et al., Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s disease, Nat. Neurosci., 2011, vol. 14, no. 1, pp. 69–76.

    Article  PubMed  Google Scholar 

  34. Kregel, K.C. and Zhang, H.J., An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations, Am. J. Physiol. Regul. Integr. Comp. Physiol., 2007, vol. 292, no. 1, pp. 18–36.

    Article  Google Scholar 

  35. Reczek, C.R. and Chandel, N.S., ROS-dependent signal transduction, Curr. Opin. Cell Biol., 2015, vol. 33, pp. 8–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Swerdlow, R.H., Burns, J.M., and Khan, S.M., The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives, Biochim. Biophys. Acta, 2014, vol. 1842, no. 8, pp. 1219–1231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sierra, A., Gottfried-Blackmore, A.C., McEwen, B.S., and Bulloch, K., Microglia derived from aging mice exhibit an altered inflammatory profile, Glia, 2007, vol. 55, no. 4, pp. 412–424.

    Article  PubMed  Google Scholar 

  38. Kilbride, S.M., Telford, J.E., Tipton, K.F., and Davey, G.P., Partial inhibition of complex I activity increases Ca2+-independent glutamate release rates from depolarized synaptosomes, J. Neurochem., 2008, vol. 106, no. 2, pp. 826–834.

    Article  CAS  PubMed  Google Scholar 

  39. Moreira, P.I., Honda, K., Liu, Q., Santos, M.S., Oliveira, C.R., Aliev, G., Nunomura, A., Zhu, X., Smith, M.A., and Perry, G., Oxidative stress: the old enemy in Alzheimer’s disease pathophysiology, Curr. Alzheimer Res., 2005, vol. 2, no. 4, pp. 403–408.

    Article  CAS  PubMed  Google Scholar 

  40. Devi, L., Prabhu, B.M., Galati, D.F., Avadhani, N.G., and Anandatheerthavarada, H.K., Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction, J. Neurosci., 2006, vol. 26, no. 35, pp. 9057–9068.

    Article  CAS  PubMed  Google Scholar 

  41. Atamna, H. and Boyle, K., Amyloid-beta peptide binds with heme to form a peroxidase: relationship to the cytopathologies of Alzheimer’s disease, Proc. Natl. Acad. Sci. U. S. A., 2006, vol. 103, no. 9, pp. 3381–3386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cardoso, S.M. and Oliveira, C.R., The role of calcineurin in amyloid-beta-peptides-mediated cell death, Brain Res., 2005, vol. 1050, nos. 1–2, pp. 1–7.

    Article  CAS  PubMed  Google Scholar 

  43. Manczak, M., Calkins, M.J., and Reddy, P.H., Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer’s disease: implications for neuronal damage, Hum. Mol. Genet., 2011, vol. 20, no. 13, pp. 2495–2509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kolosova, N.G., Stefanova, N.A., Korbolina, E.E., Fursova, A.Zh., and Kozhevnikova, O.S., Senescenceaccelerated OXYS rats: a genetic model of premature aging and age-related diseases, Adv. Gerontol., 2014, vol. 4, no. 4, pp. 294–298.

    Article  Google Scholar 

  45. Rudnitskaya, E.A., Maksimova, K.Y., Muraleva, N.A., Logvinov, S.V., Yanshole, L.V., Kolosova, N.G., and Stefanova, N.A., Beneficial effects of melatonin in a rat model of sporadic Alzheimer’s disease, Biogerontology, 2015, vol. 16, no. 3, pp. 303–316.

    Article  CAS  PubMed  Google Scholar 

  46. Rudnitskaya, E., Muraleva, N.A., Maksimova, K.Y., Kiseleva, E., Kolosova, N.G., and Stefanova, N.A., Melatonin attenuates memory impairment, amyloid-ß accumulation, and neurodegeneration in a rat model of sporadic Alzheimer’s disease, J. Alzheimer’s Dis., 2015, vol. 47, pp. 103–116.

    CAS  Google Scholar 

  47. Stefanova, N.A., Kozhevnikova, O.S., Vitovtov, A.O., Maksimova, K.Y., Logvinov, S.V., Rudnitskaya, E.A., Korbolina, E.E., Muraleva, N.A., and Kolosova, N.G., Senescence-accelerated OXYS rats: a model of agerelated cognitive decline with relevance to abnormalities in Alzheimer disease, Cell Cycle, 2014, vol. 13, no. 6, pp. 898–909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Stefanova, N.A., Maksimova, K.Y., Kiseleva, E., Rudnitskaya, E.A., Muraleva, N.A., and Kolosova, N.G., Melatonin attenuates impairments of structural hippocampal neuroplasticity in OXYS rats during active progression of Alzheimer’s disease-like pathology, J. Pineal Res., 2015, vol. 59, no. 2, pp. 163–177.

    Article  CAS  PubMed  Google Scholar 

  49. Stefanova, N.A., Muraleva, N.A., Korbolina, E.E., Kiseleva, E., Maksimova, K.Y., and Kolosova, N.G., Amyloid accumulation is a late event in sporadic Alzheimer’s disease-like pathology in nontransgenic rats, Oncotarget, 2015, vol. 6, no. 3, pp. 1396–1413.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Stefanova, N.A., Muraleva, N.A., Skulachev, V.P., and Kolosova, N.G., Alzheimer’s disease-like pathology in senescence-accelerated OXYS rats can be partially retarded with mitochondria-targeted antioxidant SkQ1, J. Alzheimer’s Dis., 2014, vol. 38, no. 3, pp. 681–694.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular Mechanisms of Aging Sector, Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences, pr. Lavrentyeva 10, Novosibirsk, 630090, Russia

    N. A. Stefanova & N. G. Kolosova

  2. Cytology and Genetics Department, Biological Branch, Novosibirsk State University, ul. Pirogova 2, Novosibirsk, 630090, Russia

    N. G. Kolosova

Authors
  1. N. A. Stefanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. G. Kolosova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N. G. Kolosova.

Additional information

Original Russian Text © N.A. Stefanova, N.G. Kolosova, 2016, published in Vestnik Moskovskogo Universiteta. Biologiya, 2016, No. 1, pp. 6–13.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stefanova, N.A., Kolosova, N.G. Evolution of Alzheimer’s disease pathogenesis conception. Moscow Univ. Biol.Sci. Bull. 71, 4–10 (2016). https://doi.org/10.3103/S0096392516010119

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.3103/S0096392516010119

Keywords

Search

Navigation